The major goals of this work are the elucidation of the roles of COX-1 and COX-2 in the tumorigenesis process. Epidemiological studies in humans have shown a marked decrease in several types of cancers that correlates with the use of nonsteroidal antiinflammatory drugs (NSAIDs). We have demonstrated that COX-1 and COX-2 deficiencies reduce skin tumorigenesis and intestinal tumorigenesis and believe this reduction is due to premature terminal differentiation of initiated cells. This premature onset of terminal differentiation would continually remove initiated cell from the replicative population and decrease tumor growth and numbers. Because the prostaglandins (PG)produced via the cyclooxygenases cause their effects by interacting with a family of G protein coupled receptors we identified the PGE2 receptors present in the skin and fornd that EP2 and EP4 were elevated in tumors compared to normal skin. However, studies with specific receptor agonist indicate that only EP2 contributes to tumor growth. By studying the signaling pathways activated by EP2 we have found Ras levels and activation are significantly increased by EP2 ligand binding. This represents the first report of oncogene activation by a prostaglandin mediated pathway.
